Drawing A Bead On Side Effects
In her 14-year fight against breast cancer, Janet Powell has become all too familiar with the foul side effects of chemotherapy. Treatments left her wracked with nausea, hot flashes, and uncontrollable tingling in her hands and feet. Powell's only relief came in 2002, when she enrolled in a clinical trial of Abraxane, a drug derived from a popular chemo treatment but reengineered to cause fewer side effects. "All of a sudden I started feeling really good," says Powell, a 57-year-old secretary in Greenville, Tex. "I almost forgot I had cancer."
Abraxane, approved by the Food & Drug Administration in January, is part of a growing class of drugs designed to improve on flawed, older ones. American Pharmaceutical Partners Inc. (APPX ) (APP) created it by reformulating Taxol, a 13-year-old chemo drug, to remove the ingredient that makes patients feel sick.
The battle against harmful side effects is emerging as a promising new frontier for the drug industry. Some companies, like APP, aim to remove noxious chemicals. Others hope to salvage bad drugs by improving the way the body digests them. Yet others use what they have learned about side effects to overhaul their development process. Together, these strategies could resurrect hundreds of pharmaceutical flameouts -- drugs that were pulled from the market, or never made it out of the lab because of adverse reactions.
There couldn't be a better time for companies to zero in on drug side effects. Ever since Merck & Co. (MRK ) withdrew Vioxx last year, the pharmaceutical industry has been pelted with one safety concern after another. The latest: On Mar. 25, Abbott Laboratories (ABT ) said it would stop selling a 30-year-old drug called Cylert that can cause fatal liver problems.
An Abbott spokeswoman says the company will discontinue Cylert, used to treat attention deficit hyperactivity disorder, because of declining sales. But the withdrawal came just days after a consumer group petitioned the FDA to pull it. Now, Johnson & Johnson (JNJ ) is facing questions about one of its fast-growing cardiac treatments. All told, the FDA has issued 23 safety alerts this year -- three times as many as it put out by this time last year.
The number of such warnings would fall dramatically if side effects could be engineered out. And that challenge has inspired some ingenious approaches. For example, ARYx Therapeutics Inc. in Santa Clara, Calif., is trying to correct flaws in the way some drugs are broken down in the liver. Its first target is Propulsid, an acid-reflux treatment that J&J pulled in 2000.
It turns out that when patients ingested Propulsid along with certain other drugs, the combination depleted the supply of an important but rare enzyme in the liver that breaks down the drug. So too much Propulsid passed into the blood, where it touched off other problems: It blocked the flow of potassium to the heart, causing irregular, potentially fatal heartbeats. By redesigning one section of the Propulsid molecule, ARYx created a drug that fights acid reflux, bypasses the problematic enzyme, and causes no heart risk. The drug is still in mid-stage trials, but if it works, the market potential could be huge: Propulsid hit nearly $1 billion in annual sales before it was yanked.
As pharmaceutical companies decode the secrets of side effects, they're using that knowledge to design safer drugs from the get-go. At Merck, scientists are collecting data about patterns of genes that become active or inactive when drugs cause serious effects. The database helps them to flag new molecules that cause similar genetic patterns, allowing them to throw out potentially harmful compounds. And a handful of pharma companies has licensed a screening system developed by the Salk Institute for Biological Studies in San Diego. The test pinpoints drugs likely to trip a potentially lethal chain of events, in which the body flushes out other drugs the patient is taking before they can work.
Despite the promise of such tools, getting reformulated drugs to market will require more than technical prowess. Some enterprising drug designers may be blocked by broad patents that other pharma companies hold. Then there's the regulatory minefield. Even though the drugs are based on existing treatments, no one can predict whether the reformulations will work until they undergo years of human testing.
With so many reformulated drugs still unproven, all eyes are on the recent O.K. for APP's Abraxane. The compound is designed to fix a core problem with Taxol: Before it can be injected into patients, it must be dissolved in a solvent so noxious it can cause life-threatening allergic reactions. Dr. Patrick Soon-Shiong, founder and chairman of the Schaumburg (Ill.) biotech, figured out how to replace the solvent with nanoparticles of human protein, each one-hundredth the size of a red blood cell, that envelop the drug and deliver it straight to tumors. The protein, albumin, normally carries nutrients to tumors that help them to grow. "We're tricking the tumor into believing it's eating a nutrient, when in fact it's getting the drug," Soon-Shiong explains.
Several cancer centers are now testing Abraxane to see if the gentler formulation will save lives by allowing doctors to deliver higher doses of chemo over shorter periods of time. And APP hopes to apply its technology to other cancer treatments on the market, as well as some that never made it into human testing because no one could figure out how to dissolve them. Abraxane could bring in sales of up to $155 million this year and grow 40% annually for the next several years, analysts estimate. As more and more patients find their lives threatened by treatments that were supposed to save them, companies that blaze new pathways to safety will be richly rewarded.
By Arlene Weintraub in New York, with Michael Arndt in Chicago